In DepthCOVID-19

New challenges emerge for planned human challenge trials

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Science  04 Dec 2020:
Vol. 370, Issue 6521, pp. 1150
DOI: 10.1126/science.370.6521.1150

Science's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation

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Earlier challenge trials deliberately infected volunteers with flu virus and other pathogens.


In the early days of the COVID-19 pandemic, tens of thousands of young volunteers offered to risk their health by letting scientists intentionally infect them with the pandemic coronavirus, hoping to speed the hunt for a vaccine or treatment. Several research groups announced plans to run these so-called human challenge trials, even as some scientists questioned whether they could be conducted ethically.

Now, with recent news that conventional human trials have produced several promising vaccines, scientists are debating whether planned challenge trials are still needed. In the United States, one nascent effort is on hold. In the United Kingdom, however, researchers say they are moving ahead. “There are still many strong arguments for pursuing” challenge trials, says immunologist Christopher Chiu of Imperial College London, leader of the proposed U.K. trial.

In traditional human trials, researchers give volunteers either a vaccine or a placebo, then wait months or longer for enough cases to emerge to gather statistically rigorous results. Challenge trials can move faster by first vaccinating volunteers and then intentionally exposing them to SARS-CoV-2 in a controlled setting. Researchers would then closely monitor the volunteers for days or weeks.

But challenge trials are also rife with ethical concerns. For example, because there are no reliable treatments for severe COVID-19, people who volunteer to test a vaccine could die if they get sick. So, medical authorities around the world have adopted a cautious approach. Even 1 year after the outbreak began, no such trial is underway. Meanwhile, 11 vaccines have entered the final phase of conventional human testing, with promising results already emerging: Four vaccines have shown up to 95% efficacy (see p. 1151).

Proponents say challenge experiments could still advance science and save lives. They could be used to compare the effectiveness of different vaccines, for instance, and help quickly screen the most promising second-generation candidates from the dozens now in the works. Challenge studies could also help answer unknowns, such as whether vaccines block infection entirely or simply prevent people from getting sick.

It's hard to use large trials to determine whether a vaccinated person still sheds the virus, says epidemiologist Marc Lipsitch of Harvard University. “It's almost prohibitively expensive because in a 30,000-person trial you have to test 30,000 people a week,” he says.

The initiative Chiu heads, the Human Challenge Consortium, is backed by £33 million from the U.K. government. If regulators approve, scientists could infect the first volunteers in January 2021. The first studies, involving up to 100 volunteers ages 18 to 30, would identify the lowest viral dose needed to cause an infection. Then they could move forward with head-to-head comparisons of different vaccine candidates. Although the experiment won't replace traditional efficacy trials, it could highlight which vaccines warrant further investment, Chiu says.

Chiu is comfortable with intentionally infecting people with SARS-CoV-2 because there is growing evidence that young adults have a low risk of serious illness. He consulted with researchers at King's College London who help manage an app tracking COVID-19 symptoms for more than 4 million people. Among 650 young adults with confirmed cases, 90% had no symptoms after 3 weeks, and the symptoms of a few “outliers” resolved after a few months, Chiu says.

In the United States, however, the encouraging recent vaccine results have put a damper on human challenge trials. A month ago, virologist Matthew Memoli put the final touches on plans for a challenge trial at the National Institute of Allergy and Infectious Diseases (NIAID). But Anthony Fauci, head of NIAID, and Francis Collins, head of the National Institutes of Health, recently suggested the experiment is no longer necessary.

That's welcome news to some, who fear that challenge trials present serious risks to volunteers. Others, however, say the apparent success of some vaccines could strengthen the case for challenge trials. Once viable vaccines are available, it's harder to justify continuing with traditional trials, in which thousands of people are given a placebo while others are vaccinated, says bioethicist Nir Eyal of Rutgers University, New Brunswick. “Are you going to hope that tens of thousands of people will altruistically be willing to forgo access to a proven vaccine?” he asks.

Seema Shah, a bioethicist at Northwestern University, thinks human challenge trials could still be useful, but there is less urgency now. And she would like to see more ways to ensure participants' safety, such as finding biological markers for people at greater risk of getting sick. “I think I would feel more comfortable waiting a bit to see how those things developed and whether the risk could be minimized further,” she says.

Lipsitch agrees that “the immediate need is not great” for human challenge trials. But, he adds, researchers “need to keep preparing in case we have reason to start doing them.”

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